This proposal aims to develop a specific 5-hydroxytryptamine-1A (5-HT1A) receptor agonist PET probe for in vivo quantification of high affinity (HA) state in nonhuman primates. The antagonist radiotracer [11C]WAY-100635 is the most commonly used 5-HT1A ligand for in vivo PET studies. However, antagonist ligands bind both to the HA and low affinity (LA) conformation of 5-HT1A receptor with equal affinity. In contrast, agonists bind preferentially to the HA state of the receptor which is coupled to G-protein, thereby providing a more meaningful functional measure of the 5-HT1A receptor. Estimation of the sensitivity of radioligand binding to competition by intrasynaptic serotonin would make it possible to compare serotonin levels after release or depletion in healthy and diseased populations. Moreover, the estimation of occupancy of, or effects on, HA sites of the 5-HT1A receptor are valuable tools for drug development. Compared to antagonist radioligands, an agonist PET radiotracer is expected to be more sensitive for these studies. To date, there are no published reports of a successful and selective 5-HT1A agonist PET radioligand in living brain. We have designed flexible synthetic schemes for concise access to 18F and 11C analogues of several recently identified highly selective 5-HT1A agonists. MicroPET scans in adult male rats/ conventional animal dissection studies will be used for the preliminary determination of the blood brain barrier permeability and biodistribution of the radiolabeled agonists. The suitable candidates will be then evaluated in baboon as potential PET imaging probes for 5-HT1A receptors. After confirming specific brain uptake in baboon by baseline and block studies, and development of metabolite analyses, the optimal modeling method and outcome measure will be determined by measuring test/retest reproducibility, identifiability, and time stability. Based on the results, the optimal candidate for clinical studies will be used for the in vivo quantification of HA conformation of 5-HT1A receptors and tested in baboons to evaluate the sensitivity of agonist binding to changes in intra-synaptic serotonin levels. PET studies with 5-HT1A receptor agonist radiotracers are expected to offer new and more sensitive tools to study this important receptor and its role in the pathophysiology of depression, anxiety and other neuropsychiatric disorders and for 5-HT1A-targeted drug development. [unreadable] [unreadable] [unreadable]